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Begacestat (GSI-953) is a novel and potent thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase (IC50Aβ40 = 15 nM) with the potential for the treatment of Alzheimer's disease (AD).
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| ln Vivo |
Aβ40 and Aβ42 in the brain are dramatically reduced after 4 hours of benacestat (5 mg/kg, po in mice) administration (37% lowering of brain Aβ40 and 25% lowering of Aβ40 observed)[1]. When taken orally three hours prior to training, benacestat (GSI-953: 0, 2.5, 5, or 10 mg/kg, oral gavage, three hours) causes a dose-dependent reversal of contextual fear conditioning deficits. When compared to vehicle-dosed Tg2576 mice, significant impairments are seen following treatment with 2.5 mg/kg Begacestat, with partial reversal at 5 mg/kg and complete reversal at 10 mg/kg[2]. Males at all dosages show a slightly lower percentage of SP CD4+ cells (SP CD4+ cells=~11% in controls compared with ~7% to ~9% in animals dosed with Begacestat), while females at 2000 mg/kg/day show a slightly lower percentage of SP CD4+ cells (SP CD4+ cells=~10% in controls compared with ~8% in animals dosed with Begacestat)[2].
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| Animal Protocol |
Animal/Disease Models: Tg2576 mice[2]
Doses: 0, 2.5, 5, or 10 mg/kg Route of Administration: po (oral gavage) for two days Experimental Results: Resulted in a dose-dependent reversal of contextual fear conditioning deficits when compound is orally administered 3 h before training. Animal/Disease Models: SD (Sprague-Dawley) rats[2] Doses: 0, 200, 600, or 2000 mg/kg/day for 10 (5 males/group and 5 females at Route of Administration: PO for 10 (5 males/group and 5 females at 600 mg/kg/day) or 28 (10/sex/group) days . Experimental Results: A dosage-related trend of slightly lower percentages of SP CD4+ cells in males at all dosages and females at 2000 mg/kg/day was observed. |
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| Additional Infomation |
Begacestat has been used in trials studying the treatment and basic science of Alzheimer Disease.
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| Molecular Formula |
C9H8CLF6NO3S2
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|---|---|
| Molecular Weight |
391.7274
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| Exact Mass |
390.954
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| CAS # |
769169-27-9
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| PubChem CID |
11269353
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| Appearance |
White to off-white solid powder
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| LogP |
4.253
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
463
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=C(SC(=C1)Cl)S(=O)(=O)N[C@H](CO)C(C(F)(F)F)C(F)(F)F
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| InChi Key |
PSXOKXJMVRSARX-SCSAIBSYSA-N
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| InChi Code |
InChI=1S/C9H8ClF6NO3S2/c10-5-1-2-6(21-5)22(19,20)17-4(3-18)7(8(11,12)13)9(14,15)16/h1-2,4,7,17-18H,3H2/t4-/m1/s1
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| Chemical Name |
5-Chloro-N-((1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl)thiophene-2-sulfonamide
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| Synonyms |
GSI953 Begacestat GSI-953 GSI 953
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~127.64 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5528 mL | 12.7639 mL | 25.5278 mL | |
| 5 mM | 0.5106 mL | 2.5528 mL | 5.1056 mL | |
| 10 mM | 0.2553 mL | 1.2764 mL | 2.5528 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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